CN105188785B - Pharmaceutical composition comprising hyaluronic acid is used to treat black disc disease - Google Patents

Pharmaceutical composition comprising hyaluronic acid is used to treat black disc disease Download PDF

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CN105188785B
CN105188785B CN201480022838.9A CN201480022838A CN105188785B CN 105188785 B CN105188785 B CN 105188785B CN 201480022838 A CN201480022838 A CN 201480022838A CN 105188785 B CN105188785 B CN 105188785B
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hyaluronic acid
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CN105188785A (en
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N·焦尔当
P·柏拉托
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Fidia Pharmaceutical Co Ltd
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    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs

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Abstract

The pharmaceutical composition of gel form is described and claimed in the present invention, its dehydration for being used to treat degeneration of intervertebral disc, particularly nucleus pulposus and Voiding form, is referred to as " black disc disease ".These compositions include derivatives of hyaluronic acids, and it forms the hydrogel of accurate rheological properties, and described characteristic becomes the desirable material of filling nucleus pulposus.

Description

Pharmaceutical composition comprising hyaluronic acid is used to treat black disc disease
Invention field
The present invention relates to the pharmaceutical composition of form of hydrogels, and it is used to treat the de- of degeneration of intervertebral disc, particularly nucleus pulposus Water and Voiding form, it is referred to as " black disc disease (black disc disease) ".
Technical background
Generic term " backache " includes extensive obstacle, and its definition is typically uncertain, and its teiology is difficult to point Class, it is characterised by shared symptom：" backache ".The lumbosacral region of backbone is vital structure；In all transition hinges, It is to determine the part for bearing maximum pressure, but is also most movable, and this causes it exposed to continuous excess load and unbalance. The key point of backbone is interverbebral disc.It is included among all types of vertebras, and including two coaxial substructures：Outside Fibrous ring, it is around internal nucleus pulposus.Fibrous ring is the elastic fibrous tissue of layering, by with zigzag pattern (i.e. no Vertical Square To) what is arranged is rich in a series of extracellular matrix composition of azelons (mainly II Collagen Type VIs).Specifically, outside described ring Portion is made up of type i collagen fiber (being referred to as Sharpey ' s fibers), and core is made up of II Collagen Type VIs and cartilage cell.Marrow Core is gel tissue, is mainly made up of water (being about 85% volume in healthy young man), by proteoglycan matrix (mainly by saturating Bright matter hydrochlorate, chondroitin and keratan sulfate composition) absorb, by cartilage cell's generation positioned at fibrous ring innermost layer part.Marrow Core serves as supporting part, and it supports and disperseed the pressure that backbone is continuously born；Fibrous ring supports pulling force and provides mechanical support And the stability of backbone.Interverbebral disc is no blood vessel structure, and it obtains nutrition from the blood vessel of supply adjacent bone structures.
Because slight wound or simpler aging, particularly lumbosacral region, interverbebral disc are subjected to structural modification, so as to obstacle occur, Referred to as " degeneration of intervertebral disc " (Yong-Soo, Asian Spine Journal, 2009,3,39-44).It is related to a set of complicated Phenomenon, its teiology is not always likewise, and have a different Clinical symptoms.It includes the asymptomatic change found in young man Property and special pain form, concurrent obvious postural change.The latter's generally (but not always) occurs in the elderly, and can be with Simply caused by wound, abrasion, malnutrition or by the structure aging for forming interverbebral disc (as mentioned).The vertebra of diversified forms Disk denaturation includes a feature：Water content is reduced, and causes reduction and the structure for forming the protein and proteoglycans of nucleus pulposus Modification；It becomes dehydration, Voiding and lose its gel-like structure and the fine limit with fibrous ring.The denaturation of interverbebral disc Change high-visible in NMR scannings；It occurs than healthy disc integral thinned, and shows color change, becomes not With the black of the depth, this is due to the reduction of nucleus pulposus water content.This pathology is referred to as black disc disease.Absorb vibrations And providing the thinning and ability of the interverbebral disc of spinal stability reduces the release for being almost often associated with inflammatory factor, and it is produced Severe pain (Rengachary et al., Neurosurg Focus, 2002,13, E14).
In the follow-up phase of disc disease, nucleus pulposus is also possible to oppress fibrous ring (" swelling "), and it may rupture, and produces hernia Gas.
In not serious case, conservative approach is taken, based on physical treatment and Pain management, because pain is very anxious Property and allow people to lose ability.Because the anodyne of classics has very little or without effect, by injection apply ozone therapy by into Work(uses a period of time；This therapy is using the effective anti-oxidant, anti-inflammatory of ozone, so as to analgesic effect.
In the case of most serious, in addition to Pain management, finding from the point of view of functional view is effective and treats black The strategy of disc disease, i.e., at least partly reduce the cause of disease and recover core structure and the strategy of function.In most of cases In, for black disc disease with postural defect, it produces further stiff and pain in turn.
A kind of method is that administration can produce the cell of proteoglycan matrix into nucleus pulposus, such as the interstitial from marrow is done carefully Born of the same parents, if possible combination promote substrate formed molecule (such as growth factor) and inflammatory cytokine to suppress by residual cell Agent.This method attempts recoverin chitosan matrix and control pain.
However, these treatments are still experimental, it is necessary to thoroughly verify, because their (such as closing of particularly having a question In the quantity of cell used, active material and their concentration and the type of carrier).However, having to nucleus pulposus dosed cells Effect property is still disputable；As it was earlier mentioned, this structure does not include cell initially, and it is no blood vessel, it means that what is introduced is thin Blood supply of the propagation of born of the same parents depending on surrounding structure, it is believed that it is impaired under pathology.
Such a technology is more promising：Described technology be related to nucleus pulposus introduce " supporting part ", its can absorb and Scattered pressure, so as to recover the condition similar to physiological condition.
It is found by the applicant that and confirm " supporting part " that is made up of the hydrogel with following features particularly suitable for this The application of type：
It can be by minimally invasive implantation, preferably injection technique, so as to be readily extruded；
It is left in place, and is not skidded off from implant site, because it has accurate rheological charactristicses；
It has mechanical property (elasticity, compressibility), is suitable for supporting and disperses pressure again；
It is that height can be hydrated；
It is perfectly safe, and includes its unmodified form and catabolite, and described catabolite is inevitable Ground derives from physiology enzymatic activity.
Hydrogel (its effect of is proved below by applicant) is made up of derivatives of hyaluronic acids.Hyaluronic acid (HA) is Linear chain heteroglycan, is made up of the alternate residues of D- glucuronic acids and N- acetyl group-D- grape amine.It is naturally occurring in cell In the gel of periphery, (wherein it is key component) in the matrix of the connective tissue of vertebrate, joint synovia in and glass In body fluid and umbilical cord.Therefore HA plays a significant role in biologic artifact, is both supported as many histiocytic machineries, example Such as skin, tendon, muscle and cartilage, be used as viscous liquid again, absorb shake and ensure articular surface can slide more another.
Natural hyaluronic acid has extremely variable mean molecule quantity (MW), source and preparation used depending on acquisition Method, scope is 50 to 13 × 106Da。
It should be noted that this paper " mean molecule quantity " means weight average molecular weight, pass through " inner viscosity " method meter Calculate (Terbojevich et al., Carbohydr Res, 1986,363-377).
A HA essential characteristic is that chemically viewpoint sees that it can carry out a variety of modifications, changes its rheology and machinery Feature, while keep its biological property constant.
Applicant is surprisingly it has been found that many HA derivatives (ester, N- and O- sulfated derivatives, lactone known in the art Deng) in, be best suited for application described herein is by forming acyl between the carboxyl and cetylamine of glucuronic acid residue Those of amine key acquisition.Applicant is also confirmed by the way that compared with the conventionally used ozone therapy of black disc disease, these derive Thing not only causes substantially reducing for pain symptom, and produces completely unforeseen function improvement.
Detailed description of the invention
The present invention relates to the pharmaceutical composition of form of hydrogels, and it is used to treat degeneration of intervertebral disc, particularly nucleus dehydrates With Voiding form, it is referred to as " black disc disease ".Particularly pharmaceutical composition of the invention is treating black disc disease In pain therapy and correcting the pelvis projectional angle (incidence angle) and postural change related to black disc disease It is effective in required treatment.
Described composition includes derivatives of hyaluronic acids, and it forms the hydrogel with accurate rheology characteristic, and this causes It turns into the desirable material of filling nucleus pulposus.Particularly, HA derivatives used are hexadecyl amides.
As it was earlier mentioned, HA MW may range from 50 to 13 × 106Da.HA used in the present invention can be any source , such as (come from streptococcus equi (Streptococcus equi) or streptococcus zooepidemicus from cockscomb (EP138572) extraction, fermentation (zooepidemicus), EP716688) or biosynthesis (come from bacillus (Bacillus), WO2012032153, WO , and weight average molecular weight scope 400 to 3 × 10 2012032154)6Da, particularly 105Da to 106Da, and even more Particularly 500,000 to 730,000Da.
Amide derivatives used in the present invention are prepared by the latter's fraction.
Hyaluronic acid acid amides is known to technical staff；For example, a large amount of hyaluronic acid acid amides disclosed in EP1095064 The preparation of (benzyl, octyl group, dodecyl etc.).
Only the hexadecyl amide of preparation as described herein below is used according to the invention.In brief, will spread out in advance The biochemical hyaluronic acid into 4-butyl ammonium (TBA) is dissolved in dimethyl sulfoxide (DMSO), and adds first into caused solution Sulfonic acid.Then carbonyl dimidazoles are added, and by mixture under agitation in room temperature reaction 1 hour.Then cetyl is added Amine, and by mixture in 40 ° of -42 DEG C of reaction about 16-24 hours.Then NaCl saturated solution terminating reactions are added, and are added Enter absolute ethyl alcohol, derivative is separated by precipitating.Sediment is first washed with water and alcohol mixture, is then individually washed with ethanol Wash, and last high vacuum dry.
Derivatization degree is adjusted by changing amount and the reacting condition time of agents useful for same；Derivatization degree can pass through Method measurement known in the art, such as HPLC.Within the scope of the present invention, degree of amidation scope used be 0.1% to 10% mole, preferably 1% to 3% mole, lead to after hydrolyzing acid amides and being connected the hexadecylamine of release with fluorescent material Cross HPLC measurements.
Since thus obtained derivative, concentration range that hydrogel can be prepared for 0.1 to 30mg/mL, preferably 3 to 20mg/mL, and even more preferably 5 to 15mg/mL.Carrier used is preferably saline solution or phosphate buffer.
In the pharmaceutical composition of the preferable present invention, hyaluronic acid average MW scope is 500,000 to 730,000Da, Mole amide extent and scope is 1% to 3%, and hyaluronic acid hexadecyl amide concentration range is 5 to 15mg/mL.
The hydrogel of acquisition carries out the sterilization treatment of known technology after pre-filled disposable syringe is introduced, such as in height Press in sterilizer.
No matter concentration, the hydrogel of acquisition are readily extruded, there is the viscosity for ensuring that it is left in place after applying, having ensures It absorbs and the elasticity of redisperse load, and can hydrability with height；It also retains the life of starting polymer hyaluronic acid Thing characteristic, therefore be bio-compatible, biological absorbable, and completely harmless to body, either its unmodified shape After state or enzyme degraded.
In view of its peculiar property, hydrogel can be with the biology or pharmacology of the symptom for thinking to improve black interverbebral disc Active material (such as steroidal or NSAIDs, cell factor inhibitors and local anesthetic) combines.These materials can be with It is to be fitted into immediately in syringe before applied to patient, so as to which hydrogel had not only been used as treating black interverbebral disc but also is used as active material Carrier.
Some are listed below and prepares embodiment, is only used for describing purpose.
Embodiment 1
The ten of the HA that weight average molecular weight scope is 500 to 730kDa and mole amide content range is 1 to 3% The preparation of six alkylamide derivatives
By 2g, the derivative HA for being melted into TBA salt is dissolved in 200mL DMSO in advance, and 64 μ L are added into caused solution Methanesulfonic acid；Then 52mg 1,1 '-carbonyl dimidazoles are added, and are reacted at room temperature 1 hour under mild agitation.Then add 544mg hexadecylamines, and amidation process is to carry out 16-24 hours at 42 DEG C.Then NaCl saturated solutions are added to terminate Reaction, and the absolute ethyl alcohol of 1.5 times of volumes is added after 15-30 minutes, separate derivative by precipitating.Sediment is with 80:20 Ethanol/water washs for several times, is then individually washed for several times with ethanol, and finally in high vacuum and 40 DEG C of dryings.
1.2g hexadecyl amide derivatives are obtained, the degree of amidation that HPLC is measured is about 2-3% moles.
Embodiment 2
The concentration obtained as described in embodiment 1 is the preparation of the hydrogel of 8mg/mL HA hexadecyl amide derivatives
The HA hexadecyl amide derivatives obtained described in 2g such as embodiment 1 are put into suitable container, and added Enter 250mL phosphate buffers (PBS), pH 6.9.Buffer solution includes 8.5mg/mL NaCl, 0.45mg/mL Na2HPO4× 12H2O and 0.11mg/mL NaH2PO4×2H2O。
Mixture is stirred at room temperature at least 2 hours, and 60 DEG C about 1 hour.Afterwards, T is recovered to 20-25 DEG C, And stir the mixture for 2-4 hours.The caused mixture comprising 8mg/mL hyaluronic acid hexadecyl amides is dispensed into In glass syringe, then moist heat sterilization circulation (10 minutes) is carried out at about 121 DEG C.
Embodiment 3
The patient of black disc disease is suffered from relative to ozone therapy with HA hexadecyl amides：Primary Study
NMR scan for other diagnostic purposes, determine 11 waist (L3) with black disc disease patient and Treated according to following scheme.
Material and method：
Anesthetic solution (1% carbocaine)；
The γ of ozone 27；
The HA hexadecyl amides hydrogel (8mg/mL) prepared such as the description of embodiment 2；
Technology：Scintilloscope is guided to penetrate into after being anaesthetized by skin permeation；It is vertical prominent by observing lumbar region two Go out thing and determine site of puncture；
Patient is divided into two groups：
A) 6 patients are with 0.5cc Hydrogel In Treatings；
B) 5 patients treat (control) with the γ of 3cc ozone 27.
Patient's rest a few hours after treatment, and if necessary to remove the pain management based on paracetamol.It is all Patient carries out Disability evaluation (RMDQ-Roland Morris Disability Questionnaire) and pain Assessment (VAS- Visual Analogue Scale), and after 6 months, any change of sagittal plane NMR scanning evaluation pelvis projectional angles.
As a result：
RMDQ：Two groups of all patients reports reduce motility in terms of deformity and improve quality of life, it has Comparable degree.
VAS scales：Reported pain significantly mitigates all patients again, and is expected for ozone therapy group, this result , and it is certainly surprising for the A groups with derivative HA Hydrogel In Treatings, this result；
X-ray is assessed：In the patient of A groups, it was observed that the normalization of interverbebral disc；Its display is whiter in NMR scannings, Therefore it is hydrated, and it is closely similar with untreated healthy disc.The patient of A groups also goes out in terms of pelvis projectional angle It is now significant to improve.
However, these functional effects are not observed in the patient with the B groups of ozone therapy：The not only outward appearance of interverbebral disc Do not improve (normalization), actually also deteriorate in 3 cases, and treatment does not have effect to pelvis projectional angle.
Conclusion：
Although this is only the Primary Study carried out with a small amount of patient, it is evident that with hyaluronic acid cetyl Acid amides treatment not only the symptom to the patient with black disc disease and also to it is above-mentioned institute it is functional all have it is surprising Favourable effect.
Data given herein clearly prove not only to have with the treatment of hyaluronic acid hexadecyl amide and ozone therapy Comparable analgesic effect, and it is above-mentioned it is all there is the effect of unexpected, it has recovered the hydration of nucleus pulposus, and corrects The postural defect that all patients with black disc disease show.

Claims (15)

1. purposes of the pharmaceutical composition in preparation is used to treat the medicine of " black disc disease ", described pharmaceutical composition include Hyaluronic acid hexadecyl amide hydrogel, the wherein concentration range of hyaluronic acid hexadecyl amide are 0.1 to 30mg/mL, Wherein mean molecule quantity (MW) scope of hyaluronic acid is the mole amide of 500,000 to 730,000Da and hyaluronic acid Extent and scope is 0.1% to 10%.
2. the mole amide extent and scope 1% to 3% of the purposes of claim 1, wherein hyaluronic acid.
3. the purposes of claim 1, the wherein concentration range of hyaluronic acid hexadecyl amide are 3 to 20mg/mL.
4. the purposes of claim 3, the wherein concentration range of hyaluronic acid hexadecyl amide are 5 to 15mg/mL.
5. the purposes of claim 1, wherein described pharmaceutical composition include medicine or biological active agents, the medicine or life Thing active material is selected from steroidal and NSAIDs, cell factor inhibitors and local anesthetic.
6. purposes of the pharmaceutical composition in the medicine for preparing the pain for being used for treating black disc disease, described pharmaceutical composition Comprising hyaluronic acid hexadecyl amide hydrogel, the wherein concentration range of hyaluronic acid hexadecyl amide is 0.1 to 30mg/ ML, wherein hyaluronic acid mean molecule quantity (MW) scope are 500, the mole amide of 000 to 730,000Da and hyaluronic acid It is 0.1% to 10% to change extent and scope.
7. the mole amide extent and scope 1% to 3% of the purposes of claim 6, wherein hyaluronic acid.
8. the purposes of claim 6, the wherein concentration range of hyaluronic acid hexadecyl amide are 3 to 20mg/mL.
9. the purposes of claim 8, the wherein concentration range of hyaluronic acid hexadecyl amide are 5 to 15mg/mL.
10. the purposes of claim 6, wherein described pharmaceutical composition include medicine or biological active agents, the medicine or Biological active agents are selected from steroidal and NSAIDs, cell factor inhibitors and local anesthetic.
11. pharmaceutical composition is used for the corrective therapy pelvis projectional angle related to black disc disease and postural change preparing Purposes in medicine, described pharmaceutical composition include hyaluronic acid hexadecyl amide hydrogel, wherein hyaluronic acid hexadecane The concentration range of base acid amides be 0.1 to 30mg/mL, wherein mean molecule quantity (MW) scope of hyaluronic acid be 500,000 to The mole amide extent and scope of 730,000Da and hyaluronic acid is 0.1% to 10%.
12. the mole amide extent and scope 1% to 3% of the purposes of claim 11, wherein hyaluronic acid.
13. the purposes of claim 11, the wherein concentration range of hyaluronic acid hexadecyl amide are 3 to 20mg/mL.
14. the purposes of claim 13, the wherein concentration range of hyaluronic acid hexadecyl amide are 5 to 15mg/mL.
15. the purposes of claim 11, wherein described pharmaceutical composition include medicine or biological active agents, the medicine or Biological active agents are selected from steroidal and NSAIDs, cell factor inhibitors and local anesthetic.
CN201480022838.9A 2013-04-24 2014-04-23 Pharmaceutical composition comprising hyaluronic acid is used to treat black disc disease Active CN105188785B (en)

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ITPD2013A000110 2013-04-24
IT000110A ITPD20130110A1 (en) 2013-04-24 2013-04-24 PHARMACEUTICAL COMPOSITIONS INCLUDING HYALURONIC ACID FOR THE TREATMENT OF BLACK DISC
PCT/IB2014/060928 WO2014174450A1 (en) 2013-04-24 2014-04-23 Pharmaceutical compositions containing hyaluronic acid for use in the treatment of black disk disease

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CN105188785B true CN105188785B (en) 2017-11-17

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